Highlights from Recent Cancer Literature
Journal: Cancer Research (2012)

Exosomes as EducatorsExosomes are small secreted vesicles with the ability to mediate cellcell communication through the horizontal transfer of cellular factors, such as mRNAs, microRNAs, and proteins.Recent studies have highlighted an emerging role for exosomes as key regulators of tumorigenesis and metastasis; however, the underlying mechanisms by which exosomes promote these processes remain poorly understood.In order to elucidate the molecular and cellular function of tumor-derived exosomes, Peinado and colleagues investigated the role of exosomes in metastatic melanoma.The authors isolated exosomes from the plasma of patients with melanoma and found that exosome protein content was significantly higher in patients with metastatic stage IV disease.Using mass spectrometry to analyze exosomal protein content in a panel of metastatic mouse and human melanoma cell lines, the authors identified an exosome signature consisting of tryosinase-related protein-2 (TYRP2), very late antigen 4 (VLA-4), heat-shock protein 70 (HSP70), and heatshock protein 90 (HSP90) that was enriched in the exosomes of individuals with stage IV disease and showed that one of these factors, TYRP2, had the capacity to predict future metastatic disease in a retrospective analysis of stage III melanoma patients.To test whether exosomes are functionally relevant to disease progression, the authors next injected tumor-derived exosomes into mice and monitored their effects on primary tumor growth and metastasis.Strikingly, exosomes derived from metastatic melanoma cell lines dramatically increased the metastatic burden by 240-fold in the lung and promoted distribution of metastases to additional tissues.The authors show that these intravenously injected exosomes accumulated in common sites of melanoma metastasis, causing changes in the expression of genes involved in extracellular matrix remodeling, such as S100A8 and S100A9, and promoting vascular leakage.In addition, bone marrow transplantation studies revealed that tumor-derived exosomes could promote metastasis through their ability to drive bone marrow-derived progenitor cells toward a provasculogenic c-Kit þ Tie2 þ phenotype.To identify the factors responsible for this "exosomal education" of bone marrow-derived cells, the authors compared the proteomic profiles of exosomes from highly metastatic and poorly metastatic cell lines.They showed that one candidate from this screen, the Met proto-oncogene, was present in mouse bone marrow progenitor cells after exosomal treatment and was also elevated in circulating c-Kit þ Tie2 þ progenitor cells of patients with stage IV melanoma.Reducing Met levels in exosomes through short hairpin RNA-mediated silencing decreased the levels of vasculogenic precursors in the bone marrow and blood and significantly blocked the prometastatic properties of tumor-derived exosomes.Finally, the authors provide molecular insight into the mechanisms controlling exosome production, showing that the Ras-related RAB proteins, RAB27A, RAB5B, and RAB7, are overexpressed in melanoma cell lines producing high concentrations of exosomes and demonstrating that targeted knockdown of Rab27a is sufficient to reduce exosome secretion and block metastasis.Collectively, these results bring critical insight into a clinically relevant mechanism through which tumor cells promote metastatic colonization through exosomal cross-talk and provide evidence that this process can be exploited as a therapeutic target.